Chemical synthesis of morpholine derivatives

ABSTRACT

The present invention relates to a process for the preparation of mopholine derivatives of formula (I) which are useful as a therapeutic agents.

[0001] The present invention relates to a process for the preparation ofmorpholine derivatives, and in particular, the compound2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,which are useful as therapeutic agents.

[0002] Compounds of formula (I), below, which are described inInternational patent specification No. WO 95/16679 (published Jun. 22nd1995), are potent and selective substance P (or neurokinin-1) receptorantagonists.

[0003] wherein

[0004] R² and R³ are independently selected from the group consistingof:

[0005] (1) hydrogen,

[0006] (2) C₁₋₆alkyl,

[0007] (3) C₂₋₆alkenyl, and

[0008] (4) phenyl;

[0009] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0010] (1) hydrogen,

[0011] (2) C₁₋₆alkyl,

[0012] (3) fluoro,

[0013] (4) chloro,

[0014] (5) bromo,

[0015] (6) iodo, and

[0016] (7) —CF₃;

[0017] R¹¹, R¹² and R¹³ are independently selected from the groupconsisting of:

[0018] (1) hydrogen,

[0019] (2) C₁₋₆alkyl,

[0020] (3) fluoro,

[0021] (4) chloro,

[0022] (5) bromo,

[0023] (6) iodo, and

[0024] (7) —CF₃; and

[0025] Z is C₁₋₄alkyl.

[0026] In particular, the compound2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholinehas shown potential in the treatment of emesis, depression and anxiety.Substance P antagonists are also being investigated for otherneuropsychiatric diseases, including bipolar disorder and schizophrenia,as well as postherpetic neuralgia and pain.

[0027] International patent specification No. WO 95/16679 describes thepreparation of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine(hereinafter referred to as Compound A), which has the structure:

[0028] by a two-step process starting from2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine.With reference to Examples 70 and 75 in WO 95/16679, Compound A isprepared as follows:

[0029] This prior art process and in particular its requirement for ahigh temperature cyclisation step presents a number of practicaldifficulties which render it inconvenient when attempted on anythingother than a relatively small scale. Therefore, there is a need for thedevelopment of a process which is readily amenable to scale-up and hencecapable of practical application to the manufacturing plant.

[0030] The present invention accordingly provides a convenient,efficient process which utilizes a one-step alkylation with3-chloromethyl-1,2,4-triazolin-5-one at ambient temperature thatproduces compounds of formula (I), and in particular Compound A, in ahigher yield than the prior art two-step synthesis and which avoids ahigh temperature cyclisation. The novel process of the present inventionis not only more energy efficient (since it requires no heating), but itis also more productive allowing for a shorter time-cycle on large scaleand a higher operating concentration. The ability to effect the processof the present invention in one reaction vessel, in which the desiredproduct crystallises from the reaction mixture at ambient temperature isa clear advantage over the prior art synthesis.

[0031] Thus, in a first aspect of the present invention, there isprovided a process for the preparation of a compound of formula (I)

[0032] wherein

[0033] R² and R³ are independently selected from the group consistingof:

[0034] (1) hydrogen.

[0035] (2) C₁₋₆alkyl,

[0036] (3) C₂₋₆alkenyl, and

[0037] (4) phenyl;

[0038] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0039] (1) hydrogen,

[0040] (2) C₁₋₆alkyl,

[0041] (3) fluoro,

[0042] (4) chloro,

[0043] (5) bromo,

[0044] (6) iodo, and

[0045] (7) —CF₃;

[0046] R¹¹, R¹² and R¹³ are independently selected from the groupconsisting of:

[0047] (1) hydrogen,

[0048] (2) C₁₋₆alkyl,

[0049] (3) fluoro,

[0050] (4) chloro,

[0051] (5) bromo,

[0052] (6) iodo, and

[0053] (7) —CF₃; and

[0054] Z iS C₁₋₄alkyl, which comprises:

[0055] (i) reacting a compound of formula (II)

[0056] or a salt thereof, wherein R², R³, R⁶, R⁷, R⁸, R¹¹, R¹², R¹³ andZ are as previously defined, with a compound of formula (III)

[0057] wherein LG is a leaving group selected from halogen (e.g. bromo,chloro or iodo) or an alkyl- or arylsulfonate group (e.g. mesylate ortosylate), in an organic solvent and in the presence of a base; and

[0058] (ii) collecting the resultant crystalline compound of formula(I).

[0059] In a particularly preferred aspect of the present invention,there is provided a process for the preparation of the compound2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholinewhich comprises:

[0060] (i) reacting2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholineor a salt thereof, with a compound of formula (III)

[0061] as previously defined, in an organic solvent and in the presenceof a base; and

[0062] (ii) collecting the resultant crystalline2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine.

[0063] In the compounds of formulae (I) and (II), preferably R² and R³are both independently hydrogen.

[0064] In the compounds of formulae (I) and (II), preferably R⁶ and R⁷are independently selected from fluoro and —CF₃. In particular, R⁶ andR⁷ are both independently —CF₃.

[0065] In the compounds of formulae (I) and (II), preferably R⁸ ishydrogen.

[0066] In the compounds of formulae (I) and (II), preferably R¹¹ ishydrogen or fluoro.

[0067] In the compounds of formulae (I) and (II), preferably R¹² and R¹³are both independently hydrogen.

[0068] In the compounds of formulae (I) and (II), preferably Z is —CH₃.

[0069] In the compound of formula (III), preferably, the leaving groupLG is chloro.

[0070] Suitable bases of use in the above reaction include organic basesor, more preferably, inorganic bases. Suitable organic bases includediisopropylethylamine or triethylamine. Suitable inorganic bases includesodium hydride or potassium carbonate.

[0071] Suitable organic solvents of use in the above reaction includedimethylformamide (especially where an inorganic base is used) andacetonitrile (especially where an organic base is used).

[0072] Most preferably, the above reaction is effected in,dimethylformamide in the presence of potassium carbonate.

[0073] Conveniently, the above reaction is effected at room temperature.

[0074] Conveniently, the compound of formula (II), and in particular2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine,of use in step (i) of the above reaction is in the form of its freebase. Preferably the compound of formula (II), and in particular2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine,of use in step (i) of the above reaction is in the form of its(R)-camphor sulfonic acid salt. More preferably, the compound of formula(II), and in particular2-(R)-(1-(R)-(3,5-bis-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine,of use in step (i) of the above reaction is in the form of itspara-toluenesulfonic acid salt.

[0075] According to a further or alternative aspect of the presentinvention, there is provided a process for the preparation of3-chloromethyl-1,2,4-triazolin-5-one which comprises:

[0076] (i) treatment of semicarbazide hydrochloride with benyloxyacetylchloride under Schotten-Baumann conditions to givebenzyloxyacetylsemicarbazide;

[0077] (ii) cyclisation of the product of step (i) under basicconditions to give 3-benyloxymethyl-1,2,4-triazolin-5-one;

[0078] (iii) hydrogenation of the product of step (ii) to give3-hydroxymethyl-1,2,4-triazolin-5-one; and

[0079] (iv) treatment of the product of step (iii) with a chlorinatingagent to give 3-chloromethyl-1,2,4-triazolin-5-one.

[0080] According to yet a further or alternative aspect of the presentinvention, there is provided a process for the preparation of3-hydroxymethyl-1,2,4-triazol-5-one which comprises steps (i) to (iii)as described above.

[0081] In step (i) above, the Schotten-Baumann conditions preferablyinvolve use of aqueous alkali in a suitable solvent such as an ether,for example, tetrahydrofuran, at a reduced temperature, for example,between −10° C. and +10° C., preferably 0° C. A particularly suitableaqueous alkali is aqueous sodium hydroxide.

[0082] In step (ii) above, cyclisation is preferably effected in thepresence of a base such as an alkali metal hydroxide, for example,sodium hydroxide, at an elevated temperature, conveniently at reflux.

[0083] In step (iii) above, hydrogenation may be effected by catalytichydrogenation using hydrogen in a suitable organic solvent such as analcohol, for example, methanol, in the presence of a noble metalcatalyst such as palladium or platinum or an oxide thereof on a supportsuch as charcoal, and conveniently at room temperature and pressure.More preferably, the hydrogenation is effected by transfer hydrogenationin a suitable organic solvent such as an alcohol, for example, methanol,using a hydrogenation catalyst, in particular, palladium on charcoal, inthe presence of a hydrogen donor such as sodium hypophosphite,triethylammonium formate, potassium formate, ammonium formate orcyclohexene. Ammonium formate in water is especially preferred. Thetransfer hydrogenation is preferably effected at an elevatedtemperature, for example, between 50° C. and 70° C., and preferablybetween 55° C. and 60° C.

[0084] In step (iv) above, the chlorinating agent is, for example, aninorganic acid chloride such as SOCl₂, PCl₅, PCl₃ and POCl₃. Thionylchloride (SOCl₂) is particularly preferred. The reaction is preferablyeffected in an organic solvent such as acetonitrile, conveniently atroom temperature and pressure.

[0085] The following non-limiting examples illustrate processesaccording to the present invention:

EXAMPLE 1

[0086] Preparation of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine

[0087] A solution of 3-chloromethyl-1,2,4-triazolin-5-one (3.18 g) inDMF (30 ml) was added over 1 hour to a slurry of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine(R)-camphor sulfonic acid salt (15 g) and potassium carbonate (7.71 g)in DMF (100 ml) at 22° C. The reaction mixture was aged at 22° C. for 20minutes, then water (400 ml) was added over 30 minutes. Thecrystallising mixture was cooled in an ice bath, aged for 30 minutes andthe product collected by filtration. The solid title compound was washedwith water (400 ml), air dried and dried in vacuo at 45-50° C.Yield=11.4 g; 98.1% HPLC w/w assay; 93.2% assay yield: (97.1A % HPLCprofile).

EXAMPLE 2

[0088] Steps (i) and (ii) Preparation of3-benzyloxymethyl-1,2,4-triazolin-5-one

[0089] Sodium hydroxide pellets (10.83 g) were added to a cold (0° C.),vigorously stirred, solution of semicarbazide hydrochloride (15.1 g) inwater (10 ml)/THF (50 ml) under a nitrogen atmosphere. A solution ofbenzyloxyacetyl chloride (25 g) in THF (100 ml) was added over fiveminutes and the mixture aged at 0° C. for 2 hours (reaction complete byHPLC).

[0090] THF was removed under reduced pressure, 2M sodium hydroxide (60ml) was added and the solution heated to reflux temperature for 5 hours.The reaction mixture was cooled to room temperature and left to standfor 18 hours. The solution was neutralised with 6M hydrochloric acid andthe slurry cooled in an ice-bath for 1 hour. The product was collectedby filtration, washed with cold water (10 ml) and dried in vacuo.3-Benzyloxy-methyl-1,2,4-triazolin-5-one (16.7 g) was obtained in 60%yield as a white crystalline solid. mp. 190-192° C.; ¹H NMR in d₆ DMSOδ=4.20 (2H, s, PhCH ₂), 4.42 (2H, s, OCH ₂═N). 7.25 (5H. s. Ph), 11.34(1H, s, NH) and 11.50 (1H, s, NH) ppm and ¹³C NMR in d₆ DMSO, δ=64.1(OCH₂C═N), 72.4 (PhCH₂O), 128.5 (Ph), 128.6 (Ph), 129.1 (Ph), 138.5(Ph), 145.4 (C═N) and 157.1 (NHCONH) ppm; mass spectroscopy M+H=206,M+NH₁=223.

[0091] Step (iii) Preparation of 3-hydroxymethyl-1,2,4-triazolin-5-one

[0092] 3-Benzyloxymethyl-1,2,4-triazolin-5-one (31 g) and 10% palladiumon charcoal (3.1 g) were slurried in methanol (200 ml), under a nitrogenatmosphere. A solution of ammonium formate (47.7 g) in water (20 ml) wasadded and the mixture was vigorously stirred and heated to 55-60° C. 10%Palladium on charcoal (3.1 g) was added after 2 hours and at 3 hourscatalyst (1.55 g) and ammonium formate (9.5 g) in water (4 ml ) werecharged. After 4 hours the reaction mixture was cooled to roomtemperature and left, to stand overnight.. The methanol solution wasevaporated, under reduced pressure, to low volume and flushed bycontinuous addition of methanol (3L), at 50-55° C., to remove theexcesss ammonium formate. The hot mixture was filtered through solkafloc (15 g), the filtrate concentrated to low volume and solventswitched to acetonitrile (2×400 ml). The slurry was concentrated toabout 100 ml, the product collected by filtration and then dried bitvacuo. 3-Hydroxymethyl-1,2,4-triazolin-5-one (17.1 g) was obtained in98.3% yield mp. 187-189° C. (Lit=187° C.); ¹H NMR in d₆ DMSO δ=4.34 (2H,s, HOCH ₂) and 11.42 (2H, bs NH) ppm and ¹³C NMR in d₆ DMSO δ=56.3(HOCH₂), 148.5 (CH₂ C═N) and 157.1 (NHCONH) ppm: mass spectroscopyM+H=116. M+NH₁=133.

EXAMPLE 3

[0093] Preparation of 3-Chloromethyl-1,2,4-triazolin-5-one

[0094] Thionyl chloride (19.9 g) was added over five minutes to a slurryof 3-hydroxymethyl-1,2 4-triazolin-5-one (17 g) in acetonitrile (170 ml)at 20° C. under a nitrogen atmosphere. The reaction mixture was aged at20° C. for 18 hours. [Note: after 30 minutes all the starting materialhad dissolved. At 1 hour the product began to crystallise]. TLC analysis(SiO₂; ethyl acetate/methanol (9/1); I₂) indicated that the reaction wascomplete. Hexane (510 ml) was added in one portion, the reaction cooledin an ice bath for 1 hour and the product collected by filtration. Thesolid was washed with hexane (100 ml) and dried in vacuo.3-Chloromethyl-1,2,4-triazolin-5-one (17.2 g) was obtained as a whitesolid in 87.4% yield. mp 197-199° C.; ¹H NMR in d₆ DMSO δ=4.43 (2H, s,CH ₂), 11.48 (1H, s, NH) and 11.64 (1H, s, NH) ppm and ¹³C NMR in d₆DMSO, δ=37.0 (ClCH₂), 144.4 (CH₂ C═N) and 156.8 (NHCONH) ppm.

EXAMPLE 4

[0095] Alternative Preparation of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine

[0096] (1) Alternative Method using N,N-diisopropylethylamine/DMF

[0097] A solution of 3-chloromethyl-1,2,4-triazolin-5-one (2.56 g) inDMF (20 ml) was added over 1 hour to a slurry of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholinepara-toluenesulfonic acid salt (12 g) and N,N-diisopropylethylamine(5.15 g) in DMF (40 ml) at 21° C. The reaction was aged at 21-23° C. for30 minutes, then water (120 ml) was added over 20 minutes. Thecrystallising mixture was cooled in an ice bath, aged for 30 minutes andthe product, collected by filtration. The solid title compound waswashed with water (96 ml), air dried and dried in vacuo at 50° C.Yield=9.65 g; 99.7% isolated yield.

[0098] (2) Alternative Method Using Potassium Carbonate/DMF

[0099] A solution of 3-chloromethyl-1,2,4-triazolin-5-one (1.40 g) inDMF (13.5 ml) was added over 1 hour to a slurry of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholinepara-toluenesulfonic acid salt (6.77 g) and potassium carbonate (1.55 g)in DMF (27 ml) at 19° C. The reaction was aged at 19-21° C. for 30minutes, then water (81 ml) was added over 20 minutes. The crystallisingmixture was cooled in an ice bath, aged for 30 minutes and the productcollected by filtration. The solid title compound was washed with water(54 ml), air dried and dried in vacuo at 50° C. Yield=5.37 g; 98.0%,HPLC w/w assay; 96.4% assay yield.

1. A process for the preparation of a compound of formula (I)

wherein R² and R³ are independently selected from the group consistingof: (1) hydrogen. (2) C₁₋₆alkyl. (3) C₂₋₆alkenyl, and (4) phenyl; R⁶, R⁷and R⁸ are independently selected from the group consisting of: (1)hydrogen, (2) C₁₋₆alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo,and (7) —CF₃; R¹¹, R¹² and R¹³ are independently selected from the groupconsisting of: (1) hydrogen, (2) C₁₋₆alkyl, (3) fluoro, (4) chloro, (5)bromo, (6) iodo, and (7) —CF₃; and Z is C₁₋₄alkyl, which comprises: (i)reacting a compound of formula (II)

or a salt thereof, wherein R², R³, R⁶, R⁷, R⁸, R¹¹, R¹², R¹³ and Z areas previously defined, with a compound of formula (III)

 wherein LG is a leaving group selected from halogen (e.g. bromo, chloroor iodo) or an alkyl- or arylsulfonate group (e.g. mesylate ortosylate), in an organic solvent and in the presence of a base; and (ii)collecting the resultant crystalline compound of formula (I).
 2. Aprocess for the preparation of the compound2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholinewhich comprises: (i) reacting2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholineor a salt thereof, with a compound of formula (III)

 as defined in claim 1, in an organic solvent and in the presence of abase; and (ii) collecting the resultant crystalline2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine.3. A process according to claim 1 or claim 2 wherein the leaving groupLG is chloro.
 4. A process according to claim 1 or claim 2 wherein thebase is an organic base.
 5. A process according to claim 4 wherein theorganic base is selected from diisopropylethylamine or triethylamine. 6.A process according to claim 1 or claim 2 wherein the base is aninorganic base.
 7. A process according to claim 6 wherein the inorganicbase is selected from sodium hydride or potassium carbonate.
 8. Aprocess according to any one of claims 1 to 5 wherein the organicsolvent is acetonitrile.
 9. A process according to any one of claims 1to 3, 6 or 7 wherein the organic solvent is dimethylformamide.
 10. Aprocess according to claim 1 or claim 2 wherein step (i) is effected indimethylformamide in the presence of potassium carbonate.
 11. A processaccording to any one of claims 1 to 10 wherein the reaction is effectedat room temperature.
 12. A process according to any one of claims 2 to11 wherein the 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholineof use in step (i) is in the form of its free base or its (R)-camphorsulfonic acid salt or its para-toluenesulfonic acid salt.
 13. A processfor the preparation of 3-chloromethyl-1,2,4-triazolin-5-one whichcomprises: (i) treatment of semicarbazide hydrochloride withbenyloxyacetyl chloride under Schotten-Baumann conditions to givebenzyloxyacetylsemicarbazide; (ii) cyclisation of the product of step(i) under basic conditions to give3-benyloxymethyl-1,2,4-triazolin-5-one; (iii) hydrogenation of theproduct of step (ii) to give 3-hydroxymethyl-1,2,4-triazolin-5-one; and(iv) treatment of the product of step (iii) with a chlorinating agent togive 3-chloromethyl-1,2,4-triazolin-5-one.
 14. A process for thepreparation of 3-hydroxymethyl-1,2,4-triazol-5-one which comprises (i)treatment of semicarbazide hydrochloride with benyloxyacetyl chlorideunder Schotten-Baumann conditions to give benzyloxyacetylsemicarbazide;(ii) cyclisation of the product of step (i) under basic conditions togive 3-benyloxymethyl-1,2,4-triazolin-5-one; and (iii) hydrogenation ofthe product of step (ii) to give 3-hydroxymethyl-1,2,4-triazolin-5-one.15. A process according to claim 13 or 14 wherein, in step (i), theSchotten-Baumann conditions involve use of aqueous alkali in an ether,at a reduced temperature.
 16. A process according to claim 15 whereinthe aqueous alkali is aqueous sodium hydroxide.
 17. A process accordingto claim 15 or 16 wherein the ether is tetrahydrofuran.
 18. A processaccording to any one of claims 15 to 17 wherein the Schotten Baumannreaction is effected between −10° C. and +10° C.
 19. A process accordingto claim 13 or 14 wherein, in step (ii), cyclisation is effected in thepresence of a base at an elevated temperature.
 20. A process accordingto claim 19 wherein the base is an alkali metal hydroxide.
 21. A processaccording to claim 20 wherein the alkali metal hydroxide is sodiumhydroxide.
 22. A process according to any one of claims 19 to 21 whereinthe reaction is effected at reflux.
 23. A process according to claim 13or 14 wherein, in step (iii), hydrogenation is effected by catalytichydrogenation using hydrogen in an organic solvent, and in the presenceof a noble metal catalyst on a support.
 24. A process according to claim23 wherein the organic solvent is an alcohol.
 25. A process according toclaim 24 wherein the alcohol is methanol.
 26. A process according to anyone of claims 23 to 25 wherein the noble metal catalyst is palladium orplatinum or an oxide thereof.
 27. A process according to any one ofclaims 23 to 26 wherein the support is charcoal.
 28. A process accordingto any one of claims 23 to 27 wherein the reaction is effected at roomtemperature and pressure.
 29. A process according to claim 13 or 14wherein, in step (iii), hydrogenation is effected by transferhydrogenation in a organic solvent using a hydrogenation catalyst in thepresence of a hydrogen donor.
 30. A process according to claim 29wherein the organic solvent is an alcohol.
 31. A process according toclaim 30 wherein the alcohol is methanol.
 32. A process according to anyone of claims 29 to 31 wherein the hydrogenation catalyst is palladiumon charcoal.
 33. A process according to any one of claims 29 to 32wherein the hydrogen donor is selected from sodium hypophosphite,triethylammonium formate, potassium formate, ammonium formate andcyclohexene.
 34. A process according to claim 33 wherein the hydrogendonor is ammonium formate in water.
 35. A process according to any oneof claims 29 to 34 wherein the transfer hydrogenation is effected at anelevated temperature.
 36. A process according to claim 35 wherein thereaction is effected at a temperature between 50° C. and 70° C.
 37. Aprocess according to claim 13 wherein, in step (iv), the chlorinatingagent is an inorganic acid chloride.
 38. A process according to claim 37wherein the inorganic acid chloride is selected from SOCl₂, PCl₅, PCl₃and POCl₃.
 39. A process according to claims 37 or 38 wherein thereaction is preferably effected in an organic solvent.
 40. A processaccording to claim 39 wherein the organic solvent is acetonitrile.
 41. Aprocess according to any one of claims 37 to 40 wherein the reaction iseffected at room temperature and pressure.